Regulation of TRAIL-Medicated Apoptosis in Prostate Cancer by Overexpression of XIAP
Final rept. 15 Dec 2001 - 14 Dec 2005
CALIFORNIA UNIV LOS ANGELES
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Patients with prostate cancer CaP develop resistance to conventional therapies and alternative therapies, such as immunotherapy, are being actively considered. TRAIL is selectively cytotoxic to tumor cells and minimally cytotoxic to normal tissues and is a candidate for immunotherapy. CaP cells, however, are resistant to TRAIL due to antiapoptotic mechanisms such as overexpression of XIAP. This proposal investigated the mechanism by which XIAP regulates resistance to TRAIL and the findings demonstrate that TRAIL resistance is regulated by the expression of the TRAIL receptor DR5. The regulation of DR5 was found to be under the control of the transcription repressor YY1. Inhibition of NF-954B inhibited both YY1 and XIAP and sensitized the cells with TRAIL-induced apoptosis. We demonstrate that YY1 regulates the transcription of DR5 via a YY1 DNA-binding site on the DR5 promoter. The clinical importance of XIAP expression in prostate cancer tissue was examined in tissue microarrays and we demonstrate its prognostic significance in prostate cancer patients. This also correlated with the overexpression of YY1 which also showed its prognostic significance in prostate cancer patients. In addition, we have demonstrated that cytokines derived from prostate cancer andor from the tumor microenvironment regulate the constitutive activation of NF-954B and downstream XIAP and YY1 and regulate resistance to TRAIL. Overall, our findings identify new therapeutic targets for TRAIL.
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